Introduction:
The Nanomaterial Toxicity Core is part of the Harvard-MIT Nanomaterials
Consortium, funded by the NCI. It allows investigators the ability to rapidly
characterize the potential nanomaterial toxicity of novel nanotechnology
formulations using a standard panel of in vitro and in vivo assays.
Toxicity of nanomaterials must be evaluated early in the formulation process.
Nanomaterial toxicity may be due to chemical composition (eg heavy metals) or nanoscale properties (eg inhalation).
The facility is directed by Dr Sangeeta Bhatia and Dr David Housman. Collaborators include Dr Monty Krieger,
Dr Jennifer All-port Anderson and Dr Rod Bronson.
Basal Toxicity:
Small molecules and possibly nanomaterials, exhibit basal toxicity and tissue
specific toxicity. Basal toxicity occurs when fuctions common to all cells are afftected.
The Multicenter Evaluation of in vitro Cytotoxicity Program (MEIC) tested a battery of 50
different chemicals with 61 different in vitro test assays in 29 different laboratories,
and compared its results to the human clinical LC50 values reported in a series of papers
published in 1999. The major findings showed that 80% of compounds acted through basal
toxicity, and that human cell line assays gave the best prediction of human toxicity acute
lethal peak concentrations in humans. Basal toxicity can be predicted using any human cell
line (preferably HeLa or HepG2) with a greater than 10 hour exposure.
Tissue Specific Toxicity:
At this stage in addition to basal toxicity testing, we are offering two tissue specific tests:
hepatocyte toxicity and macrophage toxicity. We believe hepatocytes and macrophages will be
two major sites of clearance and detoxification in vivo.
Hepatocyte Testing:
Hepatocytes cultured in vitro lose their morphology and function within a few days,
this has made it difficult to assess liver toxicity in vitro. However, it has been shown
that co-culture with stromal cells help stabilize the hepatocyte phenotype, as shown below.
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Compounds will be exposed for 24 hours to co-cultured hepatocytes after 6 days, and
mitochondrial activity assessed.
Macrophage Testing:
Compounds will be tested on the human macrophage cell line U937. Activation and
endocytosis assays will be used to test functionality. |
